DESCRIPTION (applicant's abstract): Emerging clinicopathological studies of major depression in Alzheimer's disease (AD+D) suggest that the development of this behavioral complication of AD is associated with degeneration of the brainstem aminergic nuclei and the relative preservation of the cholinergic bnM. The neuropathologic and related neurochemical correlates of AD+D appear to be relatively specific for this condition, and may explain aspects of the course and treatment responsiveness of major depression in this context. Family histories of major depression may also be more common for AD+D patients, suggesting an interaction between a preexisting familial vulnerability and key neurodegenerative events in the pathogenesis of AD+D. The Lewy body variant (ADLBV) has been reported to be accompanied by more aggressive degeneration of the brainstem aminergic nuclei and a higher prevalence of major depression than AD alone. If confirmed, the latter observations would strengthen the relationship of degeneration of the brainstem aminergic nuclei to the development of AD+D. We propose to continue our clinicopathologic studies of these relationships and to evaluate their generalizability using autopsy-confirmed AD/ADLBV cases and controls who were prospectively characterized by a consortium of four NIA-funded ADCs/ADRCs. Moreover. we will test the hypothesis that the severity/ chronicity of major depression in AD is correlated with the extent of degeneration of the brainstem aminergic nuclei. To assess the specificity of these findings for depression, we will also explore the morphologic and neurochemical correlates of psychosis and other behavioral abnormalities in AD. In addition to family history studies we will determine whether the emergence of AD+D is influenced by the APOE genotype of AD patients. We will also continue our investigation of the role of apoptosis in neuronal loss from the brainstem aminergic nuclei in AD. Our data suggest that AD+D patients have increased susceptibility to neuronal loss in the LC (and possibly the DR and SN) due to increased vulnerability of these cells to apoptosis. We hypothesize that this enhanced vulnerability to apoptotic cell death results from a reduction in cellular protective mechanisms as reflected by a reduced proportion of neurons that manifest the upregulation of Bcl-2. The long-term goals of the proposed research plan are to better define the biological substrates of AD+D, to facilitate the development of more effective treatments, and to provide additional insight into the clinical biology of depression in the elderly.